KCNQ1 Variant R116C Detail

We estimate the penetrance of LQTS for KCNQ1 R116C is 77%. We are unaware of any observations of this variant in individuals. R116C is not present in gnomAD. R116C has not been functionally characterized. This residue is located in a Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R116C around 77% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.91 1.0 -2 0.884 84
PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance density is our previously published method to calculate the average LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

Reported Carrier Data

PubMed ID Year Carriers Unaffected LQT1 Other Disease
LITERATURE, COHORT, AND GNOMAD: - 0 0 0
VARIANT FEATURES ALONE: - 10 3 7 -
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

R116C has 41 previously observed neighbors within 15 angstroms

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. NOTE: some residues appear multiple times at different distances. This results from the fact that the functional KV7.1 channel is a homotetramer and occasionally the same residue from multiple subunits is present within the 15A window. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

Neighbor Distance (Angstroms) Variants Observed in Individuals
116 0
112 5
117 6 P117L,
111 6 Y111C,
115 6 E115A, E115G,
244 7
118 8
181 9 R181C,
114 9
108 9 G108S,
180 10
113 10
243 10 R243H, R243C, R243P, R243S,
119 10 G119R, G119V,
122 10 C122Y,
110 11 V110I,
177 11 S177F,
178 11 A178T, A178del,
174 11 R174H, R174C, R174L,
246 12
245 12 G245V,
184 12 Y184S, Y184C, Y184D, Y184H,
109 12 R109C, R109L,
126 12 H126D,
183 13 K183R,
193 13 F193L, F193L, F193L,
242 13 D242N, D242Y,
179 13 G179S,
196 13
107 13 Q107H, Q107H,
249 13 R249S, R249S,
182 14
198 14 I198V, I198T,
123 14
241 14 V241F, V241I, V241G,
121 14
106 15
105 15
125 15
247 15 T247I,
173 15